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???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
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dc.contributor.advisor | 林琬琬(Wan-wan Lin) | |
dc.contributor.author | Hyemin Lee | en |
dc.contributor.author | 李惠珉 | zh_TW |
dc.date.accessioned | 2021-07-10T21:53:31Z | - |
dc.date.available | 2021-07-10T21:53:31Z | - |
dc.date.copyright | 2019-08-28 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-08-13 | |
dc.identifier.citation | REFERENCES
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77269 | - |
dc.description.abstract | B淋巴細胞誘導的成熟蛋白-1 (Blimp-1)是一種轉錄抑制因子,在調節各種免疫細胞的發育和功能中起著至關重要的作用。目前,關於角質形成細胞和癌細胞中Blimp-1表達和細胞功能的調節的理解有限。在這項研究中,我們發現EGF、PMA、TGF-β、TNF-、H2O2、UVB和TLR激活劑(LPS、polyIC、CpG)可以上調HaCaT角質形成細胞及鱗狀細胞癌(Cal-27和SAS)中Blimp-1的蛋白質和mRNA水平。儘管這些刺激物可以同時激活細胞中的EGFR,但不是所有刺激物誘導Blimp-1表達的作用與EGFR相關。研究顯示PMA在Cal-27細胞及TGF-β在前列腺癌細胞PC3及 LNCaP的作用與內生性EGFR的活化有關,相反的,EGFR的抑制劑易瑞沙 (Iressa) 並未抑制PMA和TNF-在HaCaT引起的Blimp-1誘導作用,也不抑制TNF-α 和TGF-β分別在Cal-27 及 SAS細胞的作用。另一方面,Syk抑制劑可降低PMA在HaCaT細胞中誘導的Blimp-1基因表達,而不影響TNF-的作用。於Blimp-1報告基因的分析得知,AP-1參與EGF刺激HaCaT細胞的Blimp-1基因表達。共軛顯微鏡之研究結果顯示Blimp-1依不同細胞可以表現在細胞核及細胞質中,而SAS細胞在PMA及TNF-α刺激下,Blimp-1會由細胞質轉移到細胞核中。此外,Blimp-1基因靜默時會增強角質細胞和癌細胞的遷移。所有這些結果顯示Blimp-1基因可以受各種刺激劑而增加基因及蛋白表現,且在細胞遷移中起負面的調節作用。值得注意的是,TGF-β活化EGFR的作用方式與其他的刺激劑不同,TGF-β的作用是以增加EGFR的蛋白量所致,而其他的刺激劑則是直接對EGFR產生transactivation。功能研究表明Blimp-1基因靜默不影響細胞存活,但增加癌細胞的增生,促進TGF-β刺激細胞的遷移、侵入及上皮細胞間質轉化。總之,多種刺激劑可以誘導Blimp-1的基因表現,而在某些細胞種類及刺激條件下需要內生性的EGFR活性,且Blimp-1在角質形成細胞和癌細胞中扮演負向調節細胞遷移的角色。 | zh_TW |
dc.description.abstract | B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional repressor, and plays a crucial role in the regulation of development and functions of various immune cells. Currently, there is limited understanding about the regulation of Blimp-1 expression and cellular functions in keratinocytes and cancer cells. In this study, we found that EGF, PMA, TGF-β, TNF-α, H2O2, UVB, and TLR ligands (LPS, polyIC and CpG) can upregulate the protein and mRNA levels of Blimp-1 in HaCaT keratinocytes and/or Cal-27 and SAS squamous cell carcinoma (SCC). Even though all of these stimuli can transactivate EGFR, not all stimuli-induced Blimp-1 upregulation depend on the constitutive EGFR activity. We found that the Blimp-1 responses in PMA-activated Cal-27 cells as well as in TGF-β-activated prostate cancer PC3 and LNCaP cells were inhibited by iressa. In contrast, iressa did not inhibit the Blimp-1 induction responses of PMA and TNF-α in HaCaT cells nor those of TNF-α and TGF-β in Cal-27 and SAS cells, respectively. On the other hands, Syk inhibitor can reduce PMA-, but not TNF-α-induced Blimp-1 gene expression in HaCaT and Cal-27 cells. Data of reporter assay indicate that AP-1 is involved in Blimp-1 gene expression in EGF-stimulated HaCaT keratinocytes. Confocal microscopic data revealed that Blimp-1 is localized in the nuclei and cytosol depending on cell types, and can be translocated from the cytosol to the nuclei in PMA- and TNF-α-stimulated SAS cells. Furthermore, Blimp-1 silencing enhances keratinocytes and cancer cell migration. All these findings suggest that Blimp-1 gene expression can respond to various stimuli and Blimp-1 plays a negative role in cell migration. Of note, different from other stimuli which directly transactivates EGFR activity, the effects of TGF-β in increasing EGFR activity in SAS, PC3 and LNCaP cells are resulting from the upregulation of EGFR protein. Functional study revealed that silencing Blimp-1 can not only increase cell proliferation, but also accelerate cell migration and TGF-β-induced EMT in prostate cancer cells. In conclusion, Blimp-1 can be upregulated via gene transcription by various stimuli, and in some cases depending on the EGFR activity. Blimp-1 may act as a brake on keratinocyte and cancer cell migration. | en |
dc.description.provenance | Made available in DSpace on 2021-07-10T21:53:31Z (GMT). No. of bitstreams: 1 ntu-108-R06443023-1.pdf: 4638181 bytes, checksum: f90e009ec2e9776f78312922943d2867 (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | Table of contents
口試委員會審定書…………………………………………………………… 2 Abbreviations……………………………………………… 4 Abstract…………………………………………………… 6 中文摘要…………………………………………………… 8 Introduction……………………………………………… 9 Research Motivation…………………………………… 15 Materials and Methods………………………………… 16 Results…………………………………………………… 23 Discussion………………………………………………… 33 Figures…………………………………………………… 41 Appendix…………………………………………………… 60 Reference………………………………………………… 66 | |
dc.language.iso | en | |
dc.title | Blimp-1在角質形成細胞和癌細胞中的調節和細胞功能 | zh_TW |
dc.title | Regulation and cellular functions of Blimp-1 in keratinocytes and cancer cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 吳青錫,蔡丰喬,蔡幸真 | |
dc.subject.keyword | B淋巴細胞誘導的成熟蛋白-1, | zh_TW |
dc.subject.keyword | Blimp-1, | en |
dc.relation.page | 71 | |
dc.identifier.doi | 10.6342/NTU201903165 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2019-08-13 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥理學研究所 | zh_TW |
Appears in Collections: | 藥理學科所 |
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